(a) Field of the Invention
The invention relates to genes which are involved in metastasis and their uses.
(b) Description of Prior Art
Metastasis involves the dissemination of tumor cells by invasion from the primary tumor site and proliferation of these cells at distant site in the target organ. The tumoral invasion and the metastasis are a multistep process (Babai F., J. Ultrastructure Res., 1976, 56:287-303; Liotta LA, Amer. J. Pathol., 1984, 117:339-348) which requires several factors such as the liberation of the lyric enzymes in the invaded zone, a change in the motility and cellular adhesion of the tumor cell, intercellular communication and growth autonomy (Hart IR et al., Biochimica Et Biophysica Acta, 1989, 989(1):65-84).
A number of genes have been found to be associated with changes in metastatic potential. They fall into two categories: genes or gene products which are down regulated in metastatic cells and those which are up-regulated in metastatic cells. The first category includes nm23 (Steeg PS et al., J. Natl. Cancer Inst., 1988, 80:200-204), WDNM1, WDNM2 (Dear TN et al., Cancer Res., 1989, 49:5323-5328), and E-cadherin (Frixen UH et al., Journal of Cell Biology, 1991, 113(1):173-85). The other category includes pGM21 (Phillips SM et al., Journal of the National Cancer Institute, 1990, 82(3):199-203), Mts-1 (Ebralidze A et al., Genes & Development, 1989, 3(7):1086-93), hst (Murakami A et al., Cell Growth & Differentiation, 1990, 1(5):225-31), and CD44 (Gunthert U et al., Cell, 1991, 65:13). However, the gene involved in each step of the invasion and the metastasis of all types of cancer and particularly of the rhabdomyosarcoma are not all well known.
To identify such genes, differential screening of the cDNA libraries has been used successfully by several groups using malignant and non-malignant tumors or tumor cell lines that retain a certain metastatic potential, either high or low. For example, fibronectin was isolated from a anaplastic non-metastazing subline AT-1 derived from a Dunning R-3327 rat prostatic tumor cell line. Fibronectin mRNA was down-modulated in metastatic variants of rat prostate tumor cell lines (Schalken JA et al., Cancer Res., 1988, 48:2042-2046). Nm23 has been isolated from K-1735 murine melanoma cell lines with varying metastatic potential and higher expression of nm23 was associated with low metastatic potential (Steeg PS et al., J. Natl. Cancer Inst., 1988, 80:200-204). The nm23 protein demonstrate a high homology with the nucleoside diphosphate kinase from Dictyostelium (Wallet Vet al., Journal of the National Cancer Institute, 1990, 82(14):1199-20). WDNM1 and WDNM2 have been isolated from the rat mammary adenocarcinoma cell line DMBA-8 and are overexpressed in cell lines with lower metastatic potential (Dear TN et al., Cancer Res., 1989, 49:5323-5328). The full length cDNA sequence of the WDNM2 gene exhibited complete homology to the rat NAD(P)H:menadione oxidoreductase cDNA sequence(Dear TN et al., Cancer Research, 1990, 50(5):1667). Elvin et al. (Elvin P et al., Br. J. Cancer, 1988, 57:36-42) have isolated a cDNA clone corresponding to the acidic ribosomal phosphoprotein P2 which is overexpressed in colorectal carcinomas of a human liver metastases than in primary colorectal tumors and normal tissue. However, Sharp et al. (Br. J. Cancer, 1990, 61:83-88) observed that the expression of the P2 gene is higher in human breast fibroadenomas than in carcinomas of the same tissue. Using the phenolemulsion reassociation technique with two cell sublines obtained from spontaneous mouse mammary carcinoma, the cDNA mts-1 has been isolated (Ebralidze A et al., Genes & Development, 1989, 3(7):1086-93). This cDNA is homologous to the mouse Ca.sup.2+ binding protein and is overexpressed in cell lines with higher metastatic potential. Phillips et al. (Phillips SM et al., Journal of the National Cancer Institute, 1990, 82(3):199-203) have isolated by differential screening of a subtractive cDNA library constructed from a poorly metastatic rat mammary adenocarcinoma cell line (DMBA-8) and a highly metastatic variant line (DMBA-8 ascites), the clone pGM21 which is associated with high metastatic potential. Stromelysin 3 has been isolated from a human breast carcinomas and its expression is specific for stromal cells surrounding invasive but not non-invasive breast lesions (Basset Pet al., Nature, 1990, 348:699-704). Human breast carcinomas cDNA library was differentially screened with probes derived from both malignant (carcinoma) and non-malignant (fibroadenoma) tumors (Adams SM et al., Br. J. Cancer, 1992, 65:65-71). They have identified genes encoding for the elongation factor -1.alpha., human ubiquitin carboxyl-extension (Adams SM et al., Human molecular genetics, 1992, 1(2):91-96), clone bbcl (Adams SM et al., Br. J. Cancer, 1992, 65:65-71) and mitochondrial genes encoding subunit 2 cytochrome c oxydase, subunits 2 and 4 of NADH dehydrogenase and subunit 6 of F.sub.0 F.sub.1 ATPase (Sharp MGF et al., Journal of pathology, 1992, 168:163-168). Elongation factor -1.alpha., ubiquitin carboxyl-extension and bbcl are overexpressed in fibroadenomas than in carcinomas. Conversely, only the subunit 2 cytochrome c oxydase is overexpressed in carcinoma compared to fibroadenoma.
It would be highly desirable to be provided with the identification of genes implicated in the metastatis.